The innate immune system comprises those mechanisms that have evolved over millennia to provide first line defense against foreign antigens and an antigen recognition repertoire which does not diversify during the ontogeny of the individual. This is in contrast with the acquired immune system which provides later phase defense mechanisms and depends on a repertoire of antigen-specific molecules, e.g., immunoglobulins and T cell receptors that diversify over the ontogeny of the individual. Innate immune mechanisms can contribute to initiation of an antigen-specific response by the acquired immune system, for example by faciltating uptake of antigen by antigen-presenting cells (APCs), which can thereafter stimulate cognate T cells.
Opsonins of the innate immune system (“innate opsonins”) are known in the art as secreted polypeptide molecules of the innate immune system and can remain bound to an antigen and to the surface of an APC at the same time. They can thus act as “bridges”, and are thought, by virtue of this property, to promote internalization of antigens by APCs. The mode in which opsonins bind to antigens varies among opsonins, and can be covalent or noncovalent. In general, the antigen-binding moieties of innate opsonins differ from the antigen-binding moieties of immunoglobulins in that the former are relatively invariant among members of the same species, and do not undergo diversification during the ontogeny of an individual.
There have been a number of attempts to increase uptake of antigens by APCs by coupling an antigen via a non-peptide linkage to another molecule that can bind to the surface of an APC. Targeting moieties have included, for example, C3b (Jacquier-Sarlin et al., Immunol 84:164-70; Arvieux et al., Immunol 65:229-35), alpha-2 macroglobulin (Chu et al, J Immunol 152:1538-45; Chu and Pizzo, J. Immunol 150:48-58), and molecules comprising idiotypes specific for immunoglobulin Fc receptors (Squire et al., J Immunol 152:4388-96; Gosselin et al., J Immunol 149:3477-81; Snider and Segal, J Immunol 143:59-65) or class II MHC molecules (Estrada et al., Vaccine 13:901-7; Berg et al., Eur J Immunol 24:1262-8; Carayanniotis and Barber, Nature 327:59-61).
Another approach to improving uptake of antigen by APCs has been to construct chimeric polypeptides comprising an antigen and an idiotypic portion of an antibody, in which the latter is specific for class II MHC molecules (Baier et al., J Virol 69:2357-65) or an immunoglobulin Fc receptor (Liu et al., JCI 98:2001-7).
Dempsey et al. (Science 271:348-50) constructed fusion proteins between C3d and an antigen, the fusion proteins being capable of binding to CR2-bearing cells such as B cells, reasoning that the B cell costimulation provided by C3d would increase the humoral immune response to the antigen. Marked increases in antibody response were in fact observed, which were abrogated by in vivo antibody blockade of CR2.